Neuroblastoma pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2]

Pathogenesis

• Neuroblastoma arises from neural crest cells, which are normally involved in the development of the sympathetic nervous system and adrenal glands.
• Neuroblastoma is frequently observed along the sympathetic nervous system structures. Specific sites may include:

• Adrenal glands (35% of the cases)
• Retroperitoneal organs (30% of the cases):

• Organ of Zuckerkandl
• Coeliac axis
• Paravertebral sympathetic chain

• Posterior mediastinum (20% of the cases)
• Nerve tissues in the neck (1-5% of the cases)
• Nerve tissues in the pelvis (2-3% of the cases)

• Neuroblastoma tumor cells secrete catecholamines such as:

• Vanillylmandelic acid (VMA)
• Homovanillic acid (HVA)

• Neuroblastoma tumor cells may secrete vasoactive intestinal peptide (VIP) hormone.
• Neuroblastoma may demonstrate spontaneous regression from an undifferentiated state to a completely benign cellular state.
• Metastatic disease is common and has a variety of patterns:

• Bone (most common)
• Liver (diffuse infiltration that is more common in stage 4S nueroblastoma)
• Lungs and pleura (present as discrete nodules or diffuse consolidation)
• Brain and meninges (dural metastases can be diffuse of nodular)

Genetics

• Development of neuroblasotma is the result of multiple genetic mutations.
• The vast majority of neuroblastoma cases are sporadic.
• 1-2% of neuroblastoma cases may demonstrate a familial predilection.
• Genes involved in the pathogenesis of neuroblastoma include:

• NBPF10 gene chromosome 1
• KIF1B gene on chromosome 1
• ALK gene on chromosome 2
• LMO1 gene on chromosome 11
• PHOX2A gene on chromosome 11

• MYCN oncogene amplification is a common finding among neuroblastoma patients.

Associated Conditions

• Neuroblastoma is associated with a number of syndromes that include:

• Neurofibromatosis type 1 (von Recklinghausen disease)
• Beckwith-Wiedemann syndrome
• DiGeorge syndrome
• Hirschsprung disease
• Hutchinson syndrome
• Pepper syndrome

Gross Pathology

• On gross pathology, a well defined, bulky, and tan colored mass is a characteristic finding of neuroblastoma.
• Other associated findings of neuroblastoma on gross pathology may include:

• Fibrous pseudocapsule
• Necrosis
• Hemorrhage
• Calcification

Microscopic Pathology

• On microscopic histopathological analysis the presence of round blue cells separated by thin fibrous septa are characteristic findings of neuroblastoma.
• Other findings of neuroblastoma on light microscopy may include:

• Homer-Wright rosettes (rosettes with a small meshwork of fibers at the center)
• Neuropil-like stroma (paucicellular stroma with a cotton candy-like appearance)

• On electron microscopy neuroblastoma is characterized by:

• Dendritic processes with longitudinally oriented microtubules
• Membrane bound electron-dense granules that contain catecholamines
• Presence of desmosomes
• Absence of glycogen

• On immunohistochemistry neuroblastoma is characterized by:

• Protein gene product (PGP) 9.5 positivity
• Monoclonal antibody NB84 positivity
• Synaptophysin positivity
• CD99 marker negativity

• Neuroblastic tumors may be grouped according to International Neuroblastoma Pathology Classification (Shimada classification) into two groups: a schwannian stroma rich group and a schwannian stroma poor group as illustrated below:

Neuroblastic tumors

Schwannian stroma rich group

Schwannian stroma poor group

Undifferentiated neuroblastoma Poorly differentiated neuroblastoma Differentiating neuroblastoma

Nodular ganglioneuroblastoma Intermixed ganglioneuroblastoma Maturing ganglioneuroma Mature ganglioneuroma

• Based on the degree of the cellular maturity and composition, neuroblastoma may be further classified into three subtypes according to the International Neuroblastoma Pathology Classification which include:

• Undifferentiated neruoblastoma
• Poorly differentiated neuroblastoma
• Differentiating neuroblastoma

• The table below summarizes the differnces between the three histological subtypes of neurublastoma:

Subtypes	Description
Undifferentiated neuroblastoma	Completely formed by neuroblasts with no maturity of ganglion cells
Poorly differentiated neuroblastoma	Mostly formed by neuroblasts with less the 5% maturing ganglion cells
Differentiating neuroblastoma	Predominantly formed by neuroblasts but with more than 5% mature ganglion cells

Gallery

• Illustrated below is a series of microscopic images demonstrating neuroblastoma:

• 
  Adrenal neuroblastoma
• 
  Adrenal neuroblastoma
• 
  Adrenal neuroblastoma
• 
  Adrenal neuroblastoma
• 
  Adrenal neuroblastoma
• 
  Adrenal neuroblastoma
• 
  Adrenal neuroblastoma
• 
  Adrenal neuroblastoma
• 
  Adrenal neuroblastoma

References

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